rs875525

Variant names:

• chr5-14747138-C-T
• rs875525
• NM_054027.6:c.823-1176G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_054027.6(ANKH):​c.823-1176G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.349 in 152,044 control chromosomes in the GnomAD database, including 11,545 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.35 (11545 hom., cov: 33)
• Consequence: ANKH NM_054027.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.935
• Publications: 11 publications found

Genes affected

ANKH (HGNC:15492): (ANKH inorganic pyrophosphate transport regulator) This gene encodes a multipass transmembrane protein that is expressed in joints and other tissues and controls pyrophosphate levels in cultured cells. Progressive ankylosis-mediated control of pyrophosphate levels has been suggested as a possible mechanism regulating tissue calcification and susceptibility to arthritis in higher animals. Mutations in this gene have been associated with autosomal dominant craniometaphyseal dysplasia. [provided by RefSeq, Jul 2008]

ANKH Gene-Disease associations (from GenCC):

• chondrocalcinosis 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• craniometaphyseal dysplasia, autosomal dominant

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• skeletal dysplasia

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• craniometaphyseal dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.615 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKH	NM_054027.6	c.823-1176G>A		intron_variant	Intron 6 of 11	ENST00000284268.8	NP_473368.1
ANKH	XM_017009644.3	c.739-1176G>A		intron_variant	Intron 6 of 11		XP_016865133.1
ANKH	XM_011514067.2	c.823-1176G>A		intron_variant	Intron 6 of 8		XP_011512369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKH	ENST00000284268.8	c.823-1176G>A		intron_variant	Intron 6 of 11	1	NM_054027.6	ENSP00000284268.6
ANKH	ENST00000503939.5	n.335-1176G>A		intron_variant	Intron 3 of 5	3
ANKH	ENST00000515517.1	n.57-1176G>A		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes AF: 0.349 AC: 53007 AN: 151926 Hom.: 11509 Cov.: 33

Gnomad AFR AF: 0.621

Gnomad AMI AF: 0.260

Gnomad AMR AF: 0.302

Gnomad ASJ AF: 0.213

Gnomad EAS AF: 0.131

Gnomad SAS AF: 0.0909

Gnomad FIN AF: 0.246

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.254

Gnomad OTH AF: 0.327

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.349 AC: 53096 AN: 152044 Hom.: 11545 Cov.: 33 AF XY: 0.342 AC XY: 25372 AN XY: 74292

African (AFR) AF: 0.622 AC: 25763 AN: 41446

American (AMR) AF: 0.302 AC: 4611 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.213 AC: 737 AN: 3468

East Asian (EAS) AF: 0.131 AC: 678 AN: 5176

South Asian (SAS) AF: 0.0903 AC: 435 AN: 4816

European-Finnish (FIN) AF: 0.246 AC: 2599 AN: 10546

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.254 AC: 17290 AN: 68002

Other (OTH) AF: 0.324 AC: 683 AN: 2110

Alfa AF: 0.274 Hom.: 4088

Bravo AF: 0.372

Asia WGS AF: 0.159 AC: 556 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.56
DANN	Benign	0.49
PhyloP100		-0.94
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs875525; hg19: chr5-14747247;